Energy deficits occur in neurodegeneration. Since the optic nerve is composed of RGC axons, it is particularly vulnerable to energy impairment. Autosomal dominant optic nerve atrophy, Leber's Hereditary Optic Neuropathy, and ischemic optic neuropathy are major optic nerve degenerative diseases where energy deficit is important. In glaucoma, axonal transport is impaired by the ocular hypertension (OH) leading to energy decline. Quintero et al. reported that restoration of mitochondrial axonal transport by Disc1, which is a type of adaptor protein with Miro1 and Traks to support axonal transport through Kif5a, has the potential to prevent neurodegeneration in a microbead-induced OH model mouse. First, mitochondrial transport in both anterograde and retrograde directions was visualized, and the mitochondria volume was quantified in sham and OH mice. Gene-expression analysis related to axonal transport complex revealed that adaptor protein Disc1 expression was reduced in OH mice. The authors focused on the role of Disc1 and demonstrated that siRNA against Disc1 significantly reduced the velocity of anterograde axonal transport, while restoration of Disc1 by AAV gene transfection recovered axonal transport and the volume of mitochondria.
In glaucoma, the fundamental issue is the deformation of lamina cribrosa. Even if the survival of RGC soma and energy restoration are extended, the axonal deformation in the optic nerve head is critical in glaucomatous optic neuropathy
RGC survival and restored visual function by restoration of mitochondria with Disc1 supplementation were confirmed by various in vitro and in vivo physiological assays and behavioral science analysis. This excellent study is well-conducted, using several transgenic mouse lines, and revealed exciting results for neuroprotection supported by sufficient data acquisition. I believe that mitochondria have an important role in RGC survival, as demonstrated by the recovery of axonal transport in the mouse OH model. I hope the mitochondria restoration will become a therapeutic tool for the neuroprotection in several diseases. However, in glaucoma, the fundamental issue is the deformation of lamina cribrosa. Even if the survival of RGC soma and energy restoration are extended, the axonal deformation in the optic nerve head is critical in glaucomatous optic neuropathy. Because the lamina structure is not present in the mouse optic nerve, there may be a limitation to extrapolating the neuroprotective effect with Disc1 to glaucoma neuroprotection. Perhaps it will be useful for treatment of ischemic events that lead to energy depletion.